Mammalian fat cells are traditionally classified as either energy-storing white adipocytes or energy-expending brown adipocytes. Brown adipocytes express uncoupling protein-1 (UCP1), which converts biochemical energy to heat by uncoupling ATP production from the mitochondrial proton gradient (Cannon et al., 2004, Physiol Rev 84:277-359). Such thermogenesis serves to maintain body temperature in cold environmental conditions or to promote energy balance in the face of excess caloric intake. Underscoring the metabolic importance of brown fat, its genetic ablation in mice results in severe obesity accompanied by insulin resistance, hyperglycemia, hyperlipidemia, and hypercholesterolemia (Lowell et al., 1993, Nature 366:740-742; Hamann et al., 1995, Diabetes 44:1266-1273; Hamann et al., 1996, Endocrinology 137:21-29). Given the role of UCP-1 as an important uncoupling protein, adipocytes that express UCP-1 will have a thermogenic activity.
In humans, brown adipose tissue plays an important thermogenic role in infants but shrinks during postnatal development and has historically been dismissed as sparse and clinically unimportant in adults. However, recent findings have overturned this thinking and generated considerable interest in the role(s) of brown adipose tissue during adulthood. Specifically, combined use of positron-emission tomography and computed tomography (PET-CT) to monitor tumor metastasis led to serendipidous detection of highly active, putative brown fat depots in a substantial percentage of adults (Nedergaard et al., 2007, Am J Physiol Endocrinol Metab 293:E444-E452). Subsequent studies have confirmed in healthy adults that these depots are indeed UCP1-expressing, functional brown fat (Virtanen et al., 2009, N Engl J Med 360:1518-1525), with brown-adipose-tissue activity observed during cold exposure but not thermoneutral conditions in more than 90% of young men studied (van Marken Lichtenbelt et al., 2009, N Engl J Med 360:1500-1508). Moreover, retrospective analysis of nearly two thousand PET-CT scans performed for various diagnostic reasons indicates that the amount of active brown fat is inversely correlated with body-mass index, a widely used measure of overall adiposity, raising the possibility of important beneficial roles for brown fat in adult human metabolism (Cypess et al., 2009, N Engl J Med 360:1509-1517). Less clear is the role of thermogenic adipocytes (e.g., brown adipocytes or other UCP-1 expressing adipocytes) that are interspersed with white adipose tissue.
Given the important metabolic activities of thermogenic adipocytes, there is a need for agents that increase (e.g., by formation and/or increased activity) thermogenic adipocytes in vivo.